One of the most well-known and widely used class of antibacterial agents are the so-called beta-lactam antibiotics. These compounds are characterized in that they have a nucleus consisting of a 2-azetidinone (beta-lactam) ring fused to a thiazolidine, a dihydro-1,3-thiazine or other similar ring system. When the nucleus contains a thiazolidine ring, the compounds are usually referred to generically as penicillins, whereas when the nucleus contains a dihydrothiazine ring, the compounds are referred to as cephalosporins. Typical examples of penicillins which are commonly used in clinical practice are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin, amoxicillin, hetacillin and carbenicillin; typical examples of common cephalosporins are cephalothin, cephalexin and cefazolin.
However, despite the wide use and wide acceptance of the beta-lactam antibiotics as valuable chemotherapeutic agents, they suffer from the major drawback that certain members are not active against certain microorganisms. It is thought that in many instances this resistance of a particular microorganism to a given beta-lactam antibiotic results because the microorganism produces a beta-lactamase. The latter substances are enzymes which cleave the beta-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity. However, certain substances have the ability to inhibit beta-lactamases, and when a beta-lactamases inhibitor is used in combination with a penicillin or cephalosporin, it can increase or enhance the antibacterial effectiveness of the penicillin or cephalosporin against certain beta-lactamase producing microorganisms. It is considered that there is an enhancement of antibacterial effectiveness when the antibacterial activity of a combination of a beta-lactamase inhibiting substance and a beta-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components against beta-lactamase producing microorganisms.
The present invention relates to a series of bis-1,1-alkanediol esters of 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxide and penicillins commonly used in clinical practice. These esters are readily hydrolyzed in vivo to yield the penicillin and 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxide, a particularly potent inhibitor of microbial beta-lactamases which enhances the effectiveness of the penicillin. The invention further relates to intermediates useful in the preparation of these 1,1-alkanediol esters.
Bis-esters of beta-lactam antibiotics and beta-lactamase inhibiting substances have been the subject of earlier reports, in particular the bis 1,1-alkanediol esters of beta-lactam antibiotics and penicillanic acid 1,1-dioxide (British Patent Application No. 2,044,255 and U.S. Pat. No. 4,244,951). However, the present compounds show a broader spectrum of activity than these earlier compounds, for example showing a high level of activity against beta-lactamase producing strains of Pseudomonas aeruginosa and Enterobacter cloacal, organisms against which the earlier compounds show little or no activity.